US9221796B2 - Selective NR2B antagonists - Google Patents

Selective NR2B antagonists Download PDF

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US9221796B2
US9221796B2 US14/589,205 US201514589205A US9221796B2 US 9221796 B2 US9221796 B2 US 9221796B2 US 201514589205 A US201514589205 A US 201514589205A US 9221796 B2 US9221796 B2 US 9221796B2
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pyrrolidin
piperidin
fluoro
mmol
hydroxyphenyl
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US20150191452A1 (en
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Dalton King
Lorin A. Thompson, III
Jianliang Shi
Srinivasan Thangathirupathy
Jayakumar Sankara Warrier
Imadul Islam
John E. Macor
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Syngene International Ltd
Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Assigned to SYNGENE INTERNATIONAL LIMITED reassignment SYNGENE INTERNATIONAL LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THANGATHIRUPATHY, SRINIVASAN, WARRIER, Jayakumar Sankara
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Priority to US15/604,904 priority patent/US20170258777A1/en
Priority to US15/706,172 priority patent/US20180000807A1/en
Priority to US15/846,672 priority patent/US20180110766A1/en
Priority to US15/971,067 priority patent/US20180250283A1/en
Priority to US16/225,850 priority patent/US20190117638A1/en
Priority to US16/454,831 priority patent/US20190314358A1/en
Priority to US16/777,114 priority patent/US20200163949A1/en
Priority to US17/012,781 priority patent/US20210121453A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • the disclosure generally relates to compounds of formula I, including their salts, as well as compositions and methods of using the compounds.
  • the compounds are ligands for the NR2B NMDA receptor and may be useful for the treatment of various disorders of the central nervous system.
  • N-Methyl-D-aspartate (NMDA) receptors are ion channels which are gated by the binding of glutamate, an excitatory neurotransmitter in the central nervous system. They are thought to play a key role in the development of a number of neurological diseases, including depression, neuropathic pain, Alzheimer's disease, and Parkinson's disease.
  • Functional NMDA receptors are tetrameric structures primarily composed of two NR1 and two NR2 subunits. The NR2 subunit is further subdivided into four individual subtypes: NR2A, NR2B, NR2C, and NR2D, which are differentially distributed throughout the brain.
  • Antagonists or allosteric modulators of NMDA receptors, in particular NR2B subunit-containing channels, have been investigated as therapeutic agents for the treatment of major depressive disorder (G. Sanacora, 2008, Nature Rev. Drug Disc. 7: 426-437).
  • the NR2B receptor contains additional ligand binding sites in addition to that for glutamate.
  • Non-selective NMDA antagonists such as Ketamine are pore blockers, interfering with the transport of Ca ++ through the channel. Ketamine has demonstrated rapid and enduring antidepressant properties in human clinical trials as an i.v. drug. Additionally, efficacy was maintained with repeated, intermittent infusions of Ketamine (Zarate et al., 2006, Arch. Gen. Psychiatry 63: 856-864). This class of drugs, though, has limited therapeutic value because of its CNS side effects, including dissociative effects.
  • Blockade of the hERG ion channel can lead to cardiac arrythmias, including the potentially fatal Torsades de pointe, thus selectivity against this channel is critical.
  • NR2B-selective negative allosteric modulators which have a favorable tolerability profile.
  • NR2B receptor antagonists have been disclosed in PCT publication WO 2009/006437.
  • the compounds are novel and are ligands for the NR2B receptor and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.
  • the invention encompasses compounds of Formula I, including pharmaceutically acceptable salts, pharmaceutical compositions, and their use in treating disorders related to levels of tachykinins or serotonin or both.
  • One aspect of the invention is a compound of formula I
  • Ar 1 is phenyl or indanyl and is substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, and haloalkoxy
  • Ar 2 is phenyl substituted with 1 OH substituent and also substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, and haloalkoxy
  • X is a bond or C 1 -C 3 alkylene
  • n is 1 or 2
  • ring A is azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperidinyl, or homopiperazinyl and is substituted with 0-4 substituents selected from halo, alkyl, hydroxy, or alkoxy; or a pharmaceutically acceptable salt thereof.
  • Another aspect of the invention is a compound of formula I where n is 1 and ring A is piperidinyl substituted with 0-2 halo substituents.
  • Another aspect of the invention is a compound of formula I where Ar 1 is phenyl substituted with 0-3 substituents selected from cyano, halo, alkyl, haloalkyl, and haloalkoxy.
  • Another aspect of the invention is a compound of formula I where Ar 2 is p-hydroxyphenyl.
  • Another aspect of the invention is a compound of formula I where X is methylene.
  • Another aspect of the invention is the compound of formula I: (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one or a pharmaceutically acceptable salt thereof
  • variable substituent including Ar 1 , Ar 2 , Ar 3 X, and n can be used independently with the scope of any other instance of a variable substituent.
  • the invention includes combinations of the different aspects.
  • Alkyl means a straight or branched alkyl group composed of 1 to 6 carbons.
  • Alkenyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one double bond.
  • Alkynyl means a straight or branched alkyl group composed of 2 to 6 carbons with at least one triple bond.
  • Cycloalkyl means a monocyclic ring system composed of 3 to 7 carbons. Terms with a hydrocarbon moiety (e.g. alkoxy) include straight and branched isomers for the hydrocarbon portion.
  • Hydrocarbon moiety e.g. alkoxy
  • Halo includes fluoro, chloro, bromo, and iodo.
  • Haloalkyl and haloalkoxy include all halogenated isomers from monohalo to perhalo.
  • Aryl means a monocyclic or bicyclic aromatic hydrocarbon groups having 6 to 12 carbon atoms, or a bicyclic fused ring system wherein one or both of the rings is a phenyl group. Bicyclic fused ring systems consist of a phenyl group fused to a four- to six-membered aromatic or non-aromatic carbocyclic ring. Representative examples of aryl groups include, but are not limited to, indanyl, indenyl, naphthyl, phenyl, and tetrahydronaphthyl.
  • Heteroaryl means a 5 to 7 membered monocyclic or 8 to 11 membered bicyclic aromatic ring system with 1-5 heteroatoms independently selected from nitrogen, oxygen, and sulfur. Parenthetic and multiparenthetic terms are intended to clarify bonding relationships to those skilled in the art. For example, a term such as ((R)alkyl) means an alkyl substituent further substituted with the substituent R.
  • the invention includes all pharmaceutically acceptable salt forms of the compounds.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • Some Formula I compounds contain at least one asymmetric carbon atom, an example of which is shown below.
  • the invention includes all stereoisomeric forms of the compounds, both mixtures and separated isomers. Mixtures of stereoisomers can be separated into individual isomers by methods known in the art. The compounds include all tautomeric forms.
  • the invention is intended to include all isotopes of atoms occurring in the present compounds.
  • Isotopes include those atoms having the same atomic number but different mass numbers.
  • isotopes of hydrogen include deuterium and tritium.
  • Isotopes of carbon include 13 C and 14 C.
  • Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
  • Compounds of Formula I may be made by methods known in the art including those described below and including variations within the skill of the art. Some reagents and intermediates are known in the art. Other reagents and intermediates can be made by methods known in the art using readily available materials.
  • the variables (e.g. numbered “R” substituents) used to describe the synthesis of the compounds are intended only to illustrate how to make the compounds and are not to be confused with variables used in the claims or in other sections of the specification. The following methods are for illustrative purposes and are not intended to limit the scope of the invention. The schemes encompass reasonable variations known in the art.
  • Synthesis of the desired compounds I may begin with the condensation of anilines/benzyl amines I with ⁇ , ⁇ -dibromoalkanoyl chlorides III to yield amides/anilides IV, which may be cyclized to 1-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V, as shown in synthetic scheme 1.
  • the 1-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V may be reacted with (4-oxy-phenyl)cyclic amines VI in the presence of base to produce protected products VII, which may be subjected to cleavage conditions appropriate for the protecting group (PG 1 ) to generate final products I, which may be separated into individual enantiomers/diastereomers I*, as shown in synthetic scheme 2.
  • Compounds Ia may be prepared by condensing 1-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V with substituted 4(4-oxyphenyl)piperidines VIIIa-c to generate protected intermediates IX, which may be subjected to cleavage conditions appropriate for the protecting group (PG 1 ) to generate final products Ia, which may be separated into individual enantiomers/diastereomers Ia*, as shown in synthetic scheme 3.
  • the 4(4-oxyphenyl)piperidines VIIIa-c may be synthesized in turn by a sequence starting with a protected tetrahydropiperidine X, which can be hydroxylated via hydroboration/oxidation to give the protected hydroxypiperidine XI, which may be either directly transformed into the protected fluoropiperidine XII by treatment with DAST or oxidized into the protected 3-oxopiperidine XIII, which may be further transformed into protected 3,3-difluoropiperidines XIV via treatment with DAST.
  • XI, XII, and XIV may be transformed into VIIIa, VIIIb, and VIIIc, respectively, by employing cleaving conditions appropriate for the protecting group (PG 2 ), as shown in synthetic scheme 3a.
  • tetrahydropyridines X which are not commercially available may be synthesized by coupling protected bromophenols XV with protected unsaturated piperidineboronic acids XVI, as shown in synthetic scheme 4a.
  • tetrahydropyridines X which are not commercially available may be synthesized by adding the anion generated from protected bromophenols XV to a protected 4-piperidinone XVII to yield 4-phenyl-4-piperidinol XVIII, which may be dehydrated under acid conditions to yield the desired X, as shown in synthetic scheme 4b.
  • the backbone scaffold may be synthesized by condensing 1-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V with hydroxypiperidines VIIIa to yield the protected 3-fluoropiperidines IXa, which may themselves be converted to the protected 3-fluoropiperidines IXb or oxidized to the ketones XIX, which may be converted to the 3,3-difluoropiperidines Ixc, as shown in scheme 6.
  • the final compounds can then be isolated after the deprotection of IXa-c.
  • Step B 4-(4-Methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride
  • trans-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol 9 g, 30 mmol
  • methanol 150 mL
  • 10% Pd/C 4.8 g
  • the catalyst was then removed by filtration through Celite and the solvent was evaporated under reduced pressure to give (+/ ⁇ ) trans-4-(4-methoxyphenyl)-piperidin-3-ol (5.1 g, 24.6 mmol, 81% yield).
  • Step B 1-Benzyl-5-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
  • Step A tert-Butyl 3-hydroxy-3-(4-methoxyphenyl)azetidine-1-carboxylate
  • Step A tert-Butyl 4-hydroxy-4-(4-methoxy-2-methylphenyl)piperidine-1-carboxylate
  • Step B 4-(4-Methoxy-2-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride
  • Step A tert-Butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate
  • Step B 4-(3-Fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride
  • Racemic 1-benzyl-3((4-methoxyphenyl)cycloalkylamino)pyrrolidin-2-ones and -piperidones were synthesized by condensing the lactams from Table I with cyclic amines 21-28 in the presence of a hindered amine base. A representative procedure follows:
  • the intermediates C-AJ in Table 2 were prepared by combining 1-benzyl-3-bromo-pyrrolidin-2-ones and -piperidin-2-ones from Table 1 with amines 21-28.
  • Step B 1-(4-Hydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Peak 1 showed a RT of 4.65 min and Peak 2 showed a RT of 3.54 min.
  • Step A 4-(4-Methoxyphenyl)-1′-(4-methylbenzyl)-[1,3′-bipiperidin]-2′-one
  • Step B 4-(4-Hydroxyphenyl)-1′-(4-methylbenzyl)-[1,3′-bipiperidin]-2′-one
  • Step A 1′-(3-Fluoro-4-methylbenzyl)-4-(4-methoxyphenyl)-[1,3′-bipiperidin]-2′-one
  • Step B 1′-(3-Fluoro-4-methylbenzyl)-4-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one
  • Step B 1′-Benzyl-4-(4-hydroxyphenyl)-[1,3′-bipiperidin]-2′-one
  • Step B (R)-(3-(tert-butoxycarbonylamino)-4-(3,4-dimethoxybenzylamino)-4-oxobutyl)dimethylsulfonium iodide
  • Step E (R)-1-(3,4-Dimethoxybenzyl)-3-(4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Step F (R)-1-(3,4-Dihydroxybenzyl)-3-(4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Step A ( ⁇ )-rel-(3S,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-(4-nitrobenzoyloxyl)piperidine-1-carboxylate
  • Step B ( ⁇ )-rel-(3S,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
  • Step D ( ⁇ )-rel-3-((3S,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one
  • Step E ( ⁇ )-rel-1-(4-fluorobenzyl)-3-((3S,4R)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Step F 1-(4-Fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Peak-1 Peak-2, Peak-3, Peak-4
  • Step A tert-butyl 4-(3-fluoro-4-methoxyphenyl)-4-hydroxypiperidine-1-carboxylate
  • Step B 4-(3-Fluoro-4-methoxyphenyl)-1,2,3,6-tetrahydropyridine hydrochloride
  • Step D ( ⁇ )-rel-(3S,4S)-tert-butyl 4-(3-fluoro-4-methoxyphenyl)-3-hydroxypiperidine-1-carboxylate
  • Step E ( ⁇ )-rel-(3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate
  • Step F (3R,4R)-tert-Butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate and (3S,4S)-tert-butyl 3-fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine-1-carboxylate
  • Step H 3-((3S,4S)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Step I 3-((3S,4S)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Step J (S)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Example 45 The product mixture from step I was subjected to chiral separation via SFC method C-6 to give two homochiral products: Example 45, P-1 (4.1 mg) and Example 45, P-2 (7.3 mg).
  • Step K (3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidine hydrochloride
  • Step L 3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-methoxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Step M 3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Step N (S)-3-((3R,4R)-3-Fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one and (R)-3-((4R,4R)-3-fluoro-4-(3-fluoro-4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Peak-1 Peak-2, Peak-3, Peak-4
  • reaction was then quenched by the dropwise addition of 100 mL of water. Next were added sequentially 100 mL of ethanol, 100 mL of a 10% aqueous sodium hydroxide solution, and 30% hydrogen peroxide (18 mL, 180 mmol) and the mixture was stirred at reflux temperature overnight. The reaction mixture was then allowed to cool, diluted with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (500 mL).
  • Step B ( ⁇ )-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol
  • Step C ( ⁇ )-rel-(3S,4S)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
  • Step D ( ⁇ )-rel-(3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate
  • Step E (3S,4S)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate
  • Step H 3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step I 3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step J 3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step K (S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step N 3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step O (S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step A ( ⁇ )-rel-1-(3-Fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Step B ( ⁇ )-rel-1-(3-fluoro-4-methylbenzyl)-3-((3S,4S)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Step C ( ⁇ )-rel-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Step D (S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one, (S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one, (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one, and (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Step F 1-(3-Fluoro-4-methylbenzyl)-3-((3R,4R)-3-hydroxy-4-(4-hydroxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Step G 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Peak 1 Peak 2
  • Peak 3 Peak 4
  • Step A ( ⁇ )-rel-1-(4-Fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one
  • Step B ( ⁇ )-rel-3-((3S,4S)-3-Fluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one
  • Step C 3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-fluorobenzyl)pyrrolidin-2-one
  • Step D (S)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one, (S)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one, (R)-1-(4-fluorobenzyl)-3-((3S,4S)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one, and (R)-1-(4-fluorobenzyl)-3-((3R,4R)-3-hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)pyrrolidin-2-one, and (R)-1-(4-fluorobenzyl)-3-((3R,4R)-3
  • Step B 4-((3R,4R)-3-Fluoropiperidin-4-yl)phenol trifluoroacetate
  • Step D (S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one and (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylphenyl)pyrrolidin-2-one
  • Peak-1 Peak-2, Peak-3, and Peak 4
  • Step B 3-Bromo-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one
  • Step D ( ⁇ )-rel-(3S,4S)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate
  • Step E (3S,4S)-tert-Butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate and (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-fluoropiperidine-1-carboxylate
  • Step H (S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)-ethyl)pyrrolidin-2-one and (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one
  • Step K (S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)ethyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-((S)-1-(4-fluorophenyl)-ethyl)pyrrolidin-2-one
  • Peak-1 Peak-2, Peak-3, and Peak-4
  • Step B 1-Benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine
  • Step E ( ⁇ )-rel-3-((3R,4R)-3-Hydroxy-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step F 4-(4-Methoxyphenyl)-1-(1-(4-methylbenzyl)-2-oxopyrrolidin-3-yl)piperidin-3-one
  • Step G 3-(3,3-Difluoro-4-(4-methoxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step H 3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Step I (S)-3-((R)-3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one, (S)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one, (R)-3-((R)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one, and (R)-3-((S)-3,3-difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one
  • Peak-1 Peak-2, Peak-3, and Peak-4
  • Step A tert-Butyl 4-(4-(benzyloxy)phenyl)-3-oxopiperidine-1-carboxylate
  • Step B tert-Butyl 4-(4-(benzyloxy)phenyl)-3,3-difluoropiperidine-1-carboxylate
  • Step D 3-(4-(4-(Benzyloxy)phenyl)-3,3-difluoropiperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one
  • Step E 3-(3,3-Difluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(3-fluoro-4-methylbenzyl)pyrrolidin-2-one

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US10344020B2 (en) 2015-10-14 2019-07-09 Bristol-Myers Squibb Company Selective NR2B antagonists
US10501451B2 (en) 2015-10-14 2019-12-10 Bristol-Myers Squibb Company Selective NR2B antagonists

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US10344020B2 (en) 2015-10-14 2019-07-09 Bristol-Myers Squibb Company Selective NR2B antagonists
US10501451B2 (en) 2015-10-14 2019-12-10 Bristol-Myers Squibb Company Selective NR2B antagonists
US10954225B2 (en) 2015-10-14 2021-03-23 Bristol-Myers Squibb Company Selective NR2B antagonists
US10961229B2 (en) 2015-10-14 2021-03-30 Bristol-Myers Squibb Company Selective NR2B antagonists

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